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báo cáo hóa học:" Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function"

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  1. Journal of Translational Medicine BioMed Central Open Access Research Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function Maciej Kmieciak1,4, Madhu Gowda2,4, Laura Graham3,4, Kamar Godder2,4, Harry D Bear3,4, Francesco M Marincola5,4 and Masoud H Manjili*1,4 Address: 1Department of Microbiology & Immunology, Virginia Commonwealth University Massey Cancer Center, Richmond, USA, 2Department of Pediatrics, Virginia Commonwealth University Massey Cancer Center, Richmond, USA, 3Department of Surgery, Virginia Commonwealth University Massey Cancer Center, Richmond, USA, 4Department of Pathology, Virginia Commonwealth University Massey Cancer Center, Richmond, USA and 5Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Center for Human Immunology (CHI), National Institutes of Health, Bethesda, USA Email: Maciej Kmieciak - mkmieciak@vcu.edu; Madhu Gowda - MSGowda@mcvh-vcu.edu; Laura Graham - lgraham2@mcvh-vcu.edu; Kamar Godder - kgodder@mcvh-vcu.edu; Harry D Bear - hdbear@vcu.edu; Francesco M Marincola - FMarincola@cc.nih.gov; Masoud H Manjili* - mmanjili@vcu.edu * Corresponding author Published: 22 October 2009 Received: 22 July 2009 Accepted: 22 October 2009 Journal of Translational Medicine 2009, 7:89 doi:10.1186/1479-5876-7-89 This article is available from: http://www.translational-medicine.com/content/7/1/89 © 2009 Kmieciak et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Foxp3 has been suggested to be a standard marker for murine Tregs whereas its role as marker for human Tregs is controversial. While some reports have shown that human Foxp3+ T cells had no regulatory function others have shown their role in the inhibition of T cell proliferation. Methods: T cell activation was performed by means of brayostatin-1/ionomycin (B/I), mixed lymphocyte reaction (MLR), and CD3/CD28 activation. T cell proliferation was performed using BrdU and CFSE staining. Flow cytometry was performed to determine Foxp3 expression, cell proliferation, viabilities and phenotype analyses of T cells. Results: Both CD4+ and CD8+ T cells expressed Foxp3 upon activation in vitro. Expression of Foxp3 remained more stable in CD4+CD25+ T cells compared to that in CD8+CD25+ T cells. The CD4+CD25+Foxp3+ T cells expressed CD44 and CD62L, showing their effector and memory phenotypes. Both FoxP3- responder T cells and CD4+FoxP3+ T cells underwent proliferation upon CD3/CD28 activation. Conclusion: Expression of Foxp3 does not necessarily convey regulatory function in human CD4+CD25+ T cells. Increased FoxP3 on CD44+ effector and CD44+CD62L+ memory T cells upon stimulation suggest the activation-induced regulation of FoxP3 expression. including massive lymphoproliferation, diabetes, exfolia- Background In mice, scurfy mutation in forkhead/winged helix tran- tive dermatitis, thyroiditis and enteropathy. Such autoim- scription factor gene Foxp3 causes autoimmune lesions munity can be cured by a transgene encoding a wild-type Page 1 of 7 (page number not for citation purposes)
  2. Journal of Translational Medicine 2009, 7:89 http://www.translational-medicine.com/content/7/1/89 Foxp3 allele [1]. The expression of Foxp3 in CD4+CD25+ 56), PE/Cy5-CD4 (clone OKT4) and PE/Cy5-CD8 (clone T cells in wild-type mice and the diminished numbers of RPA-T8). Appropriate isotype control antibodies were these T cells in scurfy and Foxp3-knockout (Foxp3-) mice used to exclude nonspecific binding. Foxp3 intracellular suggested a role for Foxp3 in the development of regula- staining was done with PE anti-human Foxp3 Flow Kit tory T cells (Tregs) [2]. In addition, Foxp3 has been shown (Biolegend, clone 206D) according to the manufacturer's to be a specific marker for murine CD4+ Tregs because protocol. Apoptosis was determined by staining of cells activation of non-T regs did not induce Foxp3 expression with Annexin V (BD Pharmingen). [2]. Ectopic expression of Foxp3 was shown to be suffi- cient to activate a program of suppressor function in Proliferation assay peripheral murine CD4+ T cells [2]. FITC BrdU Flow Kit (BD Pharmingen) was used in prolif- eration assays. T cells were also labeled with CFSE by incu- bation at 5 × 107 cells/mL in 5 M CFSE/HBSS for 5 min In humans, the gene encoding Foxp3 was discovered dur- ing efforts to understand the genetic basis for a rare X- at room temperature. Cells were then added with an equal linked fatal autoimmune disease known as IPEX volume of FBS, followed by three washes in FBS-contain- (immune dysregulation, polyendocrinopathy, enteropa- ing HBSS. thy, X-linked) syndrome [3,4]. However, the role of Foxp3 as a key marker for Tregs in humans remains controver- Mixed lymphocyte reaction (MLR) sial. Unlike mice, activation of human CD4+ T cells by T- Blood samples were diluted two-fold with PBS and lay- cell receptor (TcR) stimulation resulted in the expression ered onto Ficoll-Hypaque. Each tube was centrifuged at of Foxp3 [5-12]. Most of these studies showed that induc- 400 g for 30 min and the lymphocytes at the interface tion of Foxp3, even in the presence of TGF-, did not cor- were collected. These cells were washed once with RPMI 1640 medium containing 100 U/ml penicillin, 100 g/ml relate with suppressive function of CD4+ T cells [6,10-12]. Although it was suggested that lack of suppression during streptomycin, and 2 mM L-glutamine. They were then resuspended at l07 cells/ml in the same medium contain- the activation-induced expression of Foxp3 in human CD4+ T cells was because of transient expression of ing 10% heat inactivated FBS. Allogeneic stimulating cells Foxp3, the observation still argues against a role for Foxp3 were irradiated in a cesium irradiator to a total dose of as key regulator of suppression in human CD4+ T cells 5,000 rad, to abolish their capacity to proliferate. Cultures were set up in flat-bottomed 24-well plates and 3 × 106 upon expression. Regardless of the status of Foxp3, many studies considered CD4+CD25high as Tregs in humans responder cells were mixed with 2 × 106 irradiated stimu- without being able to show their regulatory functions in lators in 2 mL. Cultures, set up in triplicates, were incu- vivo [13-15]. Most recently, it was reported that maternal bated for 8 days at 37°C. Control cells cultured with alloantigens promoted development of Tregs in the medium containing low dose IL-2 (20 U/mL) in order to human fetus that could suppress fetal antimaternal maintain T cell viability during a 3-day culture. No IL-2 or immunity. The authors considered CD4+CD25+Foxp3+ T anti-CD3 Ab was used in MLR samples. Some cultures were pulsed with 10 M BrdU (BD Pharmingen). cells as Tregs because of their partial suppressive function in a mixed lymphocyte reaction (MLR) in vitro [16]. These controversial reports prompted us to determine whether Statistical analysis induction of Foxp3 expression in human T cells during Statistical comparisons between groups were made using activation and during MLR may confer regulatory func- the Student t test with P < 0.0.5 being statistically signifi- tions. Our studies showed that activation-induced expres- cant. sion of Foxp3 was transient in CD8+CD25+ T cells but it was more stable in CD4+CD25+ T cells. These Foxp3+ T Results and discussion cells were mainly of effector and memory phenotypes. Activation of T cells induces expression of CD25 and Foxp3 associated with effector and memory phenotype Methods differentiation PBMC were stimulated with bryostatin-1 (5 nM) and ion- Blood samples omycin (1 M) (B/I) in the presence of 80 U/mL of IL-2 PBMC were collected from two healthy donors, and dupli- cate experiments were performed. (Peprotech) for 16 h. B/I activation mimic intracellular signals that result in T cell activation by increasing protein kinase C activity and intracellular calcium, respectively Flow cytometry [18-20]. Cells were washed three times and cultured at 106 Three-color staining and FACS analyses were performed as previously described by our group [17]. Extracellular cells/mL in complete medium with 40 U/mL IL-2 (Pepro- staining were performed using anti-human antibodies tech) for 3 days and expression of Foxp3 was determined from Biolegend: PE- and FITC-CD25 (clone BC96), PE- using flow cytometry analysis. Expression of FoxP3 was and FITC-CD44 (clone IM7), FITC-CD62L (clone DREG- also determined on freshly isolated T cells on day 0. As Page 2 of 7 (page number not for citation purposes)
  3. Journal of Translational Medicine 2009, 7:89 http://www.translational-medicine.com/content/7/1/89 shown in Fig. 1A (top panel), presence of IL-2 alone for 3 CD8+CD25+ T cells. Absolute number of T cells increased days did not markedly increase expression of Foxp3 or 3 and 6 days after the B/I stimulation and expansion in CD25 above baseline levels on day 0 (Fig. 1C). The B/I the presence of IL-2 (Fig. 1B). Activation of T cells by activation, however, induced Foxp3 and CD25 expression means of anti-CD3/CD28 Abs for 3 days produced similar in CD4+ and CD8+ T cells (Fig. 1A, middle panel). Upon results as for B/I activation by increasing B/I activation, CD4+CD25+Foxp3+ T cells were increased CD4+CD25+FoxP3+ T cells from 0.4% to 8.7% (Fig. 1C). from 1% to 23% (P = 0.016) and CD8+CD25+Foxp3+ T Phenotype analyses of T cells revealed CD44+ effector and cells were increased from 0.6% to 9% (P = 0.013). Exten- CD44+CD62L+ memory phenotypes prior to and 6 days sion of culture in the presence of IL-2 for 6 days without after the B/I activation (Fig. 1D, top panel). While effector any further stimulation retained CD4+CD25+Foxp3+ T CD4+ and CD8+ T cells were reduced after activation cells above the baseline levels in unactivated T cells (1% (18% to 9% and 21% to 13%, respectively), memory vs. 7%; P = 0.031) whereas CD8+CD25+Foxp3+ T cells CD4+ and CD8+ T cells were increased (82% to 91% and dropped to baseline levels (0.6%). These results suggest 79% to 87%, respectively). Upon B/I activation, CD4+ T that activation-induced expression of Foxp3 in cells showed a 6-fold increases of FoxP3 expression in CD4+CD25+ T cells is more stable than that in CD44+, CD62L+ phenotypes (CD44+: 2.6% to 15%; Figure 1 Foxp3 expression following T cell activation Foxp3 expression following T cell activation. T cells were isolated from healthy volunteers and split into two groups. Control group remained unactivated and cultured in the presence of IL-2 for 3 days (A; top panel) and another group was acti- vated with B/I for 16 h and cultured in the presence of IL-2 for 3 days (A; middle panel) or 6 days (A; bottom panel). Absolute numbers of CD4+ and CD8+ T cells on pooled samples were determined on days 0, 3, and 6 post-culture by flow cytometry analysis (B). Expression of FoxP3 and CD25 were determined in freshly isolated CD4+ T cells (day 0) and after a 3-day stimu- lation with anti-CD3/CD28 Abs (C). Freshly isolated and B/I-activated T cells were subjected to flow cytometry to determine T cell phenotypes (D; top panel); Foxp3+ effector and memory T cells were determined in gated CD4+Foxp3+ cells or gated CD8+Foxp3+ cells (D; bottom panel). Representative data are shown from two donors in duplicate experiments. Page 3 of 7 (page number not for citation purposes)
  4. Journal of Translational Medicine 2009, 7:89 http://www.translational-medicine.com/content/7/1/89 CD62L+: 2% to 12%). In addition, both CD4+ and CD8+ T cells showed FoxP3high expression following activation compared to FoxP3low expression on day 0 (Fig. 1D, mid- dle and bottom panels). All CD4+Foxp3+ T cells expressed CD44 among which 80% also expressed CD62L (Fig. 1D, middle panel, far right). These data show that 20% of CD4+Foxp3+ T cells are effector and 80% are memory phenotypes. A similar phenotypic trend was detected for CD8+Foxp3+ T cells, showing 100% CD44+ of which 67% were CD62L+ T cells (Fig. 1D, bottom panel, far right). These results show that 33% of CD8+Foxp3+ T cells are effector and 67% are memory phenotypes. Data presented in Figs. 1A-D suggest that increased expression of FoxP3high in effector T cells was due to the cell differentiation rather than cell prolifera- tion, because relative percent of CD44+CD62L- effector T cells decreased after B/I activation. Similar mechanism may exist in memory T cells because of the expression of FoxP3high after activation compared to FoxP3low on day 0. Activation-induced FoxP3 expression in CD4+ T cells fails to convey regulatory function in vitro T cells were labeled with CFSE and stimulated with anti- CD3 (1 ug/ml) and anti-CD28 (1 ug/ml) Abs in the pres- ence or absence of the B/I-activated CD4+CD25+FoxP3+ T cells (2:1 and 20:1 responder:suppressor ratios) for 3 days. Flow cytometry analysis showed similar rates of pro- liferation of gated CD8+ T cells in the absence or presence of inducible FoxP3+ T cells (Fig. 2A, 60% vs. 61% and 65%). The CD3/CD28 activation also induced FoxP3 expression in responder CD4+ T cells. Gated CD4+FpxP3+ T cells also showed 70-75% proliferation upon activation (Fig. 2A). Analysis of T cell apoptosis revealed similar rates of apoptosis in responder T cells in the absence or presence of CD4+FoxP3+ T cells (Fig. 2B, 57% vs. 57 and 59%). Majority of the B/I-activated CD4+FoxP3+ T cells (74-76%) were found to be apoptotic during anti-CD3/CD28 activation in co-culture with responder T cells. Figure 2 T cell proliferation in the presence of inducible CD4+FoxP3+ cells T cell proliferation in the presence of inducible CD4+FoxP3+ T cells. To perform a co-culture suppres- sion assay, responder T cells were labeled with CFSE and cul- tured in the absence or presence of different ratios of inducible FoxP3+ T cells (20:1 and 2:1) for 3 days in the pres- ence of anti-CD3/CD28 Abs. Gated CD8+ T cells showed Figure 2 CFSE dilution (A, left panel). Responder CD4+ T cells that expressed FoxP3 due to a 3-day activation were also gated and analyzed for CFSE dilution (A, right panel). Cells obtained from a co-culture suppression assay (A, left panel) were also stained for Annexin V in order to determine apop- tosis in responder CD8+ T cells (B, left panel) and the B/I- activated CD4+FoxP3+ T cells (B, right panel). Page 4 of 7 (page number not for citation purposes)
  5. Journal of Translational Medicine 2009, 7:89 http://www.translational-medicine.com/content/7/1/89 Figure 3 Foxp3 expression following allogeneic MLR Foxp3 expression following allogeneic MLR. Cells were analyzed by flow cytometry after an 8-day MLR. BrdU incorpora- tion was determined on gated CD4+CD25+ or CD8+CD25+ T cells (A; top panel). Gated CD4+ or CD8+ T cells were ana- lyzed for the detection of CD25+Foxp3+ cells (A; bottom panel). Gated CD4+ T cells (B; top panel) or CD8+ T cells (B; bottom panel) were analyzed for the expression of CD44, CD62L, Foxp3. The CD44+ and CD62L+ T cells were determined by gating on CD4+Foxp3+ or CD8+Foxp3+ T cells. Representative data are shown from two donors in duplicate experiments. T cells and 93% of CD8+CD25+ T cells showed BrdU Allogeneic activation of T cells during MLR induces Foxp3 incorporation as a result of cell proliferation. No prolifer- expression in CD4+CD25+ T cells associated with effector/ ation was detected in the responder or stimulator cells memory phenotype We performed an 8-day allogenic MLR to determine alone (data not shown). Such allogenic proliferation took whether induction of Foxp3 expression in T cells was sta- place in the presence of an activation-induced Foxp3 ble during MLR and whether such an induced Foxp3+ expression in CD4+ T cells such that 8% of CD4+ T cells expression might inhibit T cell proliferation. Responder were CD25+Foxp3+ (Fig. 3A, bottom panel). and stimulator cells were obtained from different healthy CD8+CD25+ T cells, on the other hand, did not show sta- donors. Stimulator cells were irradiated (5000 rad) and ble expression of Foxp3. These results are consistent with cultured with responder cells for 8 days in the presence of our observation in Fig. 1 showing that expression of 10 M BrdU (BD Pharmingen). Cells were then stained Foxp3 in CD4+ T cells is more stable than that in CD8+ T with relevant Abs and subjected to flow cytometry analy- cells 6-8 days following T cell activation. In previous sis. As shown in Fig. 3A (top panel) 86% of CD4+CD25+ reports, suppressive assays in vitro were conducted in the Page 5 of 7 (page number not for citation purposes)
  6. Journal of Translational Medicine 2009, 7:89 http://www.translational-medicine.com/content/7/1/89 presence of high ratios of CD4+CD25+ T cells (Tregs) to design and manuscript preparation; FMM participated in responder cells, to determine the suppressive function on study design and data analysis; MHM designed the exper- T cell activation and proliferation. Such artificial increases iments, analyzed data, and prepared the manuscript. in the ratio of CD4+CD25+ T cells to responder cells would reduce in vivo validity of the observation. The fre- All authors read and approved the final manuscript. quency of CD4+CD25+Foxp3+ T cells induced during MLR was 8% which is considered to be within the physi- Acknowledgements ologically relevant range as reported by other groups [21- This work was supported by NIH R01 CA104757 grant (M. H. Manjili) and Massey Cancer Center Pilot Project Program, 646564. We gratefully 24]. Frequency of naturally occurring Tregs in mouse is acknowledge the support of VCU Massey Cancer Centre and the Com- also around this range, yet having regulatory effects for the monwealth Foundation for Cancer Research. inhibition of autoimmunity. If Foxp3 expressing CD4+ T cells had any regulatory function, it should have inhibited References cell proliferation during the culture in vitro. Similar to B/I- 1. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko induced T cell activation, T cell phenotypes in a MLR SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F: Disruption of a new forkhead/winged-helix protein, scurfin, results in the included CD44+ effector (16%) and CD44+CD62L+ fatal lymphoproliferative disorder of the scurfy mouse. Nat memory T cells (84%) (Fig. 3B). Again, all CD4+Foxp3+ T Genet 2001, 27:68-73. cells expressed CD44 among which 90% also expressed 2. Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T CD62L (Fig. 2B). These data show that 10% of cells. Nat Immunol 2003, 4:330-336. CD4+Foxp3+ T cells are effector and 90% are memory 3. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy- Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, phenotypes. A similar phenotypic trend was detected for McEuen M, Proll S, Appleby M, Brunkow ME: X-linked neonatal CD8+Foxp3+ T cells, showing 100% CD44+ of which diabetes mellitus, enteropathy and endocrinopathy syn- 76% were CD62L+ T cells. These results show that 24% of drome is the human equivalent of mouse scurfy. Nat Genet 2001, 27:18-20. CD8+Foxp3+ T cells are effector and 76% are memory 4. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, phenotypes. Lack of regulatory function in these Foxp3+ T Helms C, Bowcock AM: JM2, encoding a fork head-related pro- cells may be because of their effector/memory phenotype tein, is mutated in X-linked autoimmunity-allergic disregula- tion syndrome. J Clin Invest 2000, 106:R75-R81. since it has been reported that expression of Foxp3 in 5. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, human memory T cells resulted in diminished suppressor Buckner JH, Ziegler SF: Induction of Foxp3 and acquisition of T regulatory activity by stimulated human CD4+CD25-T cells. activity [25]. In addition, Treg type 1 (Tr1) cells confer J Clin Invest 2003, 112:1437-1443. suppressor function in the absence of FoxP3 expression 6. Morgan ME, van Bilsen JH, Bakker AM, Heemskerk B, Schilham MW, [26]. Given the role of Foxp3 as master regulator of Treg Hartgers FC, Elferink BG, Zanden L van der, de Vries RR, Huizinga TW, Ottenhoff TH, Toes RE: Expression of FOXP3 mRNA is not lineage commitment and maintenance in mouse [27], it confined to CD4+CD25+ T regulatory cells in humans. Hum does not seem to have such bona fide regulatory function Immunol 2005, 66:13-20. 7. Roncador G, Brown PJ, Maestre L, Hue S, Martínez-Torrecuadrada JL, for Treg lineage commitment in human T cells. Ling KL, Pratap S, Toms C, Fox BC, Cerundolo V, Powrie F, Banham AH: Analysis of FOXP3 protein expression in human Conclusion CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol 2005, 35:1681-1691. In conclusion, the present study shows that Foxp3 expres- 8. Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, Stray-Ped- sion is not a reliable marker for human Tregs. T cell acti- ersen A, Ocheltree EL, Greenberg PD, Ochs HD, Rudensky AY: Sin- vation, CD4+ T cells in particular, is associated with the gle-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell develop- expression of Foxp3 in effector/memory T cells without ment. Proc Natl Acad Sci USA 2006, 103:6659-6664. detectable regulatory function when present at physiolog- 9. Pillai V, Ortega SB, Wang CK, Karandikar NJ: Transient regulatory T-cells: A state attained by all activated human T-cells. Clin ically relevant ratios. Immunol 2007, 123:18-29. 10. Wang J, Ioan-Facsinay A, Voort EI van der, Huizinga TW, Toes RE: Abbreviations Transient expression of FOXP3 in human activated nonreg- ulatory CD4+ T cells. Eur J Immunol 2007, 37:129-138. PBMC: peripheral blood mononuclear cells; AICD: activa- 11. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, tion induced cell death; MLR: mixed lymphocyte reaction; Roncarolo MG, Levings MK: Activation-induced FOXP3 in T regs: regulatory T cells. human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007, 19:345-354. 12. Tran DQ, Ramsey H, Shevach EM: Induction of FOXP3 expres- Competing interests sion in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent The authors declare that they have no competing interests. but does not confer a regulatory phenotype. Blood 2007, 110:2983-2990. Authors' contributions 13. Michaëlsson J, Mold JE, McCune JM, Nixon DF: Regulation of T cell responses in the developing human fetus. J Immunol 2006, MK performed B/I activation of T cells, flow cytometry, 176:5741-5748. MLR, and BrdU proliferation assays; MG performed flow 14. Hueman MT, Stojadinovic A, Storrer CE, Foley RJ, Gurney JM, Shriver CD, Ponniah S, Peoples GE: Levels of circulating regulatory cytometry; LG performed B/I activation of T cells; KG par- CD4+CD25+ T cells are decreased in breast cancer patients ticipated in study design; HDB participated in study Page 6 of 7 (page number not for citation purposes)
  7. Journal of Translational Medicine 2009, 7:89 http://www.translational-medicine.com/content/7/1/89 after vaccination with a HER2/neu peptide (E75) and GM- CSF vaccine. Breast Cancer Res Treat 2006, 98:17-29. 15. Okita R, Saeki T, Takashima S, Yamaguchi Y, Toge T: CD4+CD25+ regulatory T cells in the peripheral blood of patients with breast cancer and non-small cell lung cancer. Oncol Rep 2005, 14:1269-1273. 16. Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, Lee TH, Nixon DF, McCune JM: Maternal alloantigens pro- mote the development of tolerogenic fetal regulatory T cells in utero. Science 2008, 322:1562-1565. 17. Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH: Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid- derived suppressor cells. Cancer Immunol Immunother 2009, 58:941-953. 18. Cantrell D: T cell antigen receptor signal transduction path- ways. Annu Rev Immunol 1996, 14:259-274. 19. Chatila T, Silverman L, Miller R, Geha R: Mechanisms of T cell acti- vation by the calcium ionophore ionomycin. J Immunol 1989, 143:1283-1289. 20. Bear HD, Roberts J, Cornell D, Tombes MB, Kyle B: Adoptive immunotherapy of cancer with pharmacologically activated lymph node lymphocytes: a pilot clinical trial. Cancer Immunol Immunother 2001, 50:269-274. 21. Toulza F, Nosaka K, Takiguchi M, Pagliuca A, Mitsuya H, Tanaka Y, Taylor GP, Bangham CR: Foxp3(+) regulatory T cells are dis- tinct from leukaemia cells in HTLV-1 associated adult T-cell leukaemia. Int J Cancer 2009, 125:2375-2382. 22. Card CM, McLaren PJ, Wachihi C, Kimani J, Plummer FA, Fowke KR: Decreased immune activation in resistance to HIV-1 infec- tion is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells. J Infect Dis 2009, 199:1318-1322. 23. Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ash- croft AJ, Owen RG, Selby PJ, Cook G: CD4(+)CD25(+)Foxp3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(- )alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br J Haematol 2009, 144:686-695. 24. Bi X, Suzuki Y, Gatanaga H, Oka S: High frequency and prolifera- tion of CD4+ FOXP3+ Treg in HIV-1-infected patients with low CD4 counts. Eur J Immunol 2009, 39:301-309. 25. Oswald-Richter K, Grill SM, Shariat N, Leelawong M, Sundrud MS, Haas DW, Unutmaz D: HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol 2004, 2:E198. 26. Roncarolo MG, Gregori S: Is FOXP3 a bona fide marker for human regulatory T cells? Eur J Immunol 2008, 38:925-927. 27. Josefowicz SZ, Rudensky A: Control of regulatory T cell lineage commitment and maintenance. Immunity 2009, 30:616-625. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes)
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